WO1992011873A1 - Echo contrast agent - Google Patents

Echo contrast agent

Info

Publication number
WO1992011873A1
WO1992011873A1 PCT/EP1992/000012 EP9200012W WO9211873A1 WO 1992011873 A1 WO1992011873 A1 WO 1992011873A1 EP 9200012 W EP9200012 W EP 9200012W WO 9211873 A1 WO9211873 A1 WO 9211873A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
characterized
preparation according
weight
negatively charged
preparation
Prior art date
Application number
PCT/EP1992/000012
Other languages
German (de)
French (fr)
Inventor
Klaus-Dieter Beller
Rudolf Linder
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/22Echographic preparations; Ultrasound imaging preparation Optoacoustic imaging preparations
    • A61K49/222Echographic preparations; Ultrasound imaging preparation Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/22Echographic preparations; Ultrasound imaging preparation Optoacoustic imaging preparations
    • A61K49/222Echographic preparations; Ultrasound imaging preparation Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/227Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric

Abstract

Described is an aqueous preparation, designed to absorb and stabilize micro-bubbles, for use as an echo contrast agent containing polyoxyethylene/polyoxypropylene polymers and negatively charged phospholipids. The preparation is suitable for imaging the left heart.

Description

Echo contrast agent

technical field

The invention relates to an aqueous preparation for receiving and Stabili tion of Mi rogasbläschen for use as echo contrast media.

State of the art

Since ultrasound suspended in liquids gas bubbles is greatly reflek¬ advantage, have been proposed as contrast agents for ultrasonic diagnosis early on aqueous formulations, the stabilized bubble Mikrogas¬ included. Micro gas bubbles can be used in aqueous preparations by reducing the surface tension, that is stabilized by the addition of suitable surfactants.

In EP-B-0077752 it is stated that aqueous solutions containing a surfactant or a surfactant mixture and in addition, a viscosity-increasing substance, have advantageous contrast-generating properties. As a candidate surfactants include non-ionic lecithins and lecithin fractions and polyoxyethylene polymers stated. In the six preparation examples of EP-B-0077752 preparations are ben angege¬ that as the surfactant in each case a pole oxyethylenpolyoxypropylen-polymer and included as a viscosity-increasing substance glucose or dextran or the polyoxyethylene ethylenpolyoxypropylen polymers themselves. Reworking of the preparation examples showed that the opacifying effect is not satisfactory. Thus the preparations of EP B-0077752 are not suitable for left heart images.

It has now surprisingly been found that aqueous preparations which older next polyoxyethylene polyoxypropylene poly contain negatively charged Phospholipi¬ de, are suitable in outstanding manner for receiving and stabilizing micro gas bubbles. Description of the Invention

Accordingly, the present invention relates to aqueous preparations for receiving and stabilizing micro gas bubbles for use as echo contrast media containing polyoxyethylene-poly ere and negatively charged phosphole pide.

arising from the claims other objects.

As a polyoxyethylene polyoxypropylene poly ere preferred are those with a mittle¬ ren molecular weight 8350-14000. Polyoxyethylenpolyoxy- propylene polymers are also known as poloxamers and are, for example under the trade name Pluronics ® (Wyandotte Chemicals Corp.) commercially erhält¬ Lich. The preparations according to the invention contain 0.1 to 10%, preferred wise 1 to 5%, polyoxyethylene polyoxypropylene poly ere. The negatively gela¬ where phospholipids are present in an amount of 0.01 to 5%, preferably 0.5 to 2%. Percentages relate to weight / Volu¬ men.

When negatively charged phospholipids phosphatidylglycerols, phosphatidylcholine dyl nositole, phosphatidylethanolamines and phosphatidylserines and the lyso forms in question. Among the negatively charged phospholipids Lysofor en negatively charged phospholipids be understood that contain only an acyl group. Lyso forms of the negatively charged phospholipids in which the acyl group is rinmoleküls bonded to the oxygen of the carbon atom 1 of the glycerol are preferred. negatively charged Phospholi¬ Particularly preferred are pide dipalmitoylphosphatidylglycerol (DPPG) and distearoylphosphatidylglycerol (DSPG), said distearoylphosphatidylglycerol (DSPG) very particularly preferred.

The preparations of the invention are distinguished over the prior art by the fact that containing ultrasound contrast agents can be produced with little mechanical effort microbubbles which produce because of their great stability long-lasting contrast and ausge¬ characterized also suitable for left heart representation. Particularly noteworthy is the formulations of the invention excellently suited for imaging of internal surface structures that are suitable as the micro gas bubbles anschei¬ Nend adhere well to surfaces to testify er¬ a revealing contrast even after rinsing of the microbubbles present in the lumen of vessels. This makes it possible for example to more clearly illustrate the dynamics of the heart even after washing out the contrast agent.

The preparations according to the invention is straightforward and can be done by the individual components are added together or sequentially in water and, if necessary, dissolved under heating and stirring. If desired, yet can be sterilized, for example, by heat sterilization.

Be particularly well suited for adjusting the isotonicity of the inventive preparations, glycerol, mannitol and ammonium salts of Ami¬ have nosäuren, preferably glycine proven.

The generation of the micro gas bubbles is advantageously carried out shortly before administration to the patient to be examined and is carried out in a manner known. If, for example provided the inventive preparation in a vial available, so the solution can be mounted together with the desired amount of air into a conventional syringe and injected again vial having a very high pressure through a narrow cannula into the Durch¬. If necessary, the mounting and Aus¬ will inject repeated several times. Alternatively, the invention may also Zube¬ TION between two syringes via a connector with a narrow cross-section or a switched between the two syringes mixing chamber back and be hergedrückt. The latter procedure leads to particularly informative ultrasound images, at the same time the yield is further increased.

As gases for generating the micro gas bubbles are all physiologically ver¬ träglichen gases come into question. The preparations of the invention are per 1 ml of foamed with 0.01 to 0.1, preferably 0.04 to 0.06 ml of gas. They are after production of the Mi preferably rogasbläschen intravenously ver¬ abreicht. Depending on the application, 1 to 20 ml, preferably 2 to 8 ml, and more preferably abreicht 5 ml of the preparations according to the invention comparable.

Of particular note is that compositions of the invention may be dosed less because of their increased compared to the prior art yield.

Examples

1. 3.0 g of polyoxyethylene-polyoxypropylene polymer having an average weight of from 8400 Mole¬ (Pluronic F68 ®), 1.0 g of dipalmitoylphosphatidylglycerol (DPPG) and 3.6 g of glycerol are added to 80 ml of water. The mixture is heated to about 80 β C and stirred until complete dissolution has taken place. After cooling ml is filled with distilled water to 100th

2. The procedure is as in Example 1, with the difference that instead of 1.0 g DPPG Sojaphosphatidylglycerol (Fa. Lucas Meyer, Hamburg) is used.

3. In 80 ml of water 1.1 g of glycine are entered. With dilute Ammo¬ niak and a pH of 6 to 7 is adjusted. 3.0 g of polyoxyethylene-polyoxypropylene polymer having a mean .Molekularge¬ weight of 8400 (Pluronic ® F68) and 1.0 g of DPPG into the solution. The mixture is heated to about 80 * C and stirred until complete dissolution has taken place. After cooling ml is filled with distilled water to 100th

4. The procedure is as in Example 3, with the difference that instead of 1.0 g DPPG Sojaphosphatidylglycerol (Fa. Lucas Meyer) is used ..

5. Add 80 ml of water 4.0 g of polyoxyethylene-polyoxypropylene polymer (Poloxamer 188, Pluronic ® F68), 1.0 g and 5.4 g of mannitol distearoylphosphatidylglycerol are entered. The mixture is heated to about 80 ° C and stirred until voll¬ permanent resolution. After cooling ml is filled with distilled water to 100th Comparative tests

The investigations were in conscious male beagle dogs (18.2 to 30.5 kg body weight) was performed. The dogs were each 5 ml of the contrast agent preparations iv nach¬ described below is applied:

A: containing a per 1000 ml of 35 g crosslinked polypeptides infusion solution for plasma substitution (Haemaccel ® from Behringwerke.) B: Echovist® (Echo contrast medium from the company Schering.) C: An aqueous solution containing 4 wt .-% poloxamer 188 (Pluronic® F68 ) and 4 wt .-% glucose (example 1 in EP 0 077 752) D: An aqueous solution containing 2 wt .-% poloxamer and 4 wt .-% glucose

(Example 2 in EP 0 077 752) E: An aqueous solution containing 1 wt .-% poloxamer and 4 wt .-% glucose

(Example 3 in EP 0 077 752) F: Inventive preparation according to Example 5

Solutions A, C, D, E and F are free of air drawn auf¬ in a first syringe. This syringe is then secured to the free end of a syringe with a second, advantage 0.18 ml containing air mixing chamber konnek-. Immediately before administration, the solutions five times from the first syringe through the mixing chamber in the second syringe and pumped back again.

The commercially available contrast medium B is prepared according to the instructions of Packungs¬ garnish.

The echocardiographic ultrasound images were taken using a sonicator Ultra¬ Sonoscope 4 was carried out with mechanical head at 3.5 MHz. The video prints of the ultrasound images obtained were evaluated for intensity Kontrast¬ densitometry evaluated. The densitometer (Gretag D182) used determines the changes in brightness (brightness) in 100 steps in a range from 0.00 to 2.50 density units (density units). The Ka¬-calibration is based on the vendor-supplied Kalibrie¬ insurance card according to DIN 16536 (calibration reference), where the value is assigned the value 0.00 the brightest white to the darkest black and 1.64. The average of four individual determinations on an area of ​​1 cm x 1 cm er¬ returns the value for each animal for the applied preparation.

The results obtained are shown in the table below.

Density intensity in arbitrary units (DU)

From the results that Echokontrast¬ the invention in contrast to the echo contrast media according to the prior art are respirable medium and therefore nen eig¬ awarded to the left heart diagnosis arises. The applicability of ultrasonic imaging in cardiac diagnosis is considerably extended by the novel ultrasound contrast agent.

Moreover, it was found that the microbubbles of the echo contrast media according to the invention appear to have a substantial affinity to the inner surfaces of vessels and cavities of the body. This has the consequence that the outlines of vessels and cavities much better and da¬ be presented with informative than was possible with contrast media according to the prior art. Is particularly advantageous here that this greatly improved representation of the surfaces of vessels and cavities still remains even if the lumen of the vessel or cavity be¬ already free of echo contrast agents. This surprising contrast of surfaces can be zen nut¬ for example, to observe the endocardium. In Figures 1 and 2, the result of an experiment for the assignment of these new contrasting of the surface structures is shown.

Figure 1 shows the echocardiographic image of the endocardium an awake beagle dog in the so called four-chamber view immediately before appearance of the first contrast after administration of 1 ml of echo contrast agent according to Example. 1

Figure 2 shows the endocardium of the animal after the echo contrast agent was already washed out from the heart.

From the comparison of the two images, it follows that an unexpected drawing of the endocardium is possible with the inventive echo contrast agents, which means a high information gain for diagnostic purposes.

Claims

claims
1. An aqueous preparation for receiving and stabilizing Mikrogasbläs¬ surfaces for use as echo contrast media containing Polyoxyethylenpoly- oxypropylene-Pol mers and negatively charged phospholipids.
2. Preparation according to claim 1, characterized in that polyoxyethylene lenpolyoxypropylen polymers are used having an average molecular weight 8350-14000.
3. Preparation according to claim 1, characterized in that polyoxyethylene lenpolyoxypropylen polymers in an amount of 0.1 to 10% (weight / Volu¬ men) are included.
4. A preparation according to claim 3, characterized in that the polyoxyalkylene-poly ethylenpolyoxypropylen ere in an amount of 1 to 5% are contained (weight / Vo¬ lumen).
5. Preparation according to claim 1, characterized in that phatidylethanolamine as negatively charged phospholipids phosphatidylglycerols, phosphatidylinositols, phosphorus and / or phosphatidylserines are included.
6. Preparation according to claim 5, characterized in that it contains as negatively charged phospholipid distearoylphosphatidylglycerol.
7. Preparation according to claim 1, characterized in that negative gela¬ Denes phospholipid in an amount of 0.01 to 5% (weight / volume) is hold ent.
8. A preparation according to claim 1, characterized in that it comprises (weight / volume Ge) contains 3% polyoxyethylene-polyoxypropylene polymers with an average molecular weight of 8,400 and 1% (weight / volume) Distearoylphosphati¬ dylglycerol.
9. Preparation according to claim 1, characterized in that the one or more negatively charged phospholipids are present as lyso form.
10. A process for preparation of an aqueous preparation for receiving and stabilizing micro bubbles for use as echo contrast media, da¬ by in that polyoxyethylene-polyoxypropylene polymers zusam¬ men with a negatively charged phospholipid and customary auxiliaries for achieving isotonicity are dissolved in water.
PCT/EP1992/000012 1991-01-09 1992-01-04 Echo contrast agent WO1992011873A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DEP4100470.1 1991-01-09
DE19914100470 DE4100470A1 (en) 1991-01-09 1991-01-09 Echo contrast agent

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
CA 2098915 CA2098915C (en) 1991-01-09 1992-01-04 Echo contrast agent
DE1992503392 DE59203392D1 (en) 1991-01-09 1992-01-04 Echo contrast agent.
EP19920901804 EP0566601B2 (en) 1991-01-09 1992-01-04 Echo contrast agent
KR930072025A KR100203221B1 (en) 1991-01-09 1992-01-04 Echo contrast agent
RU93052889A RU2091079C1 (en) 1991-01-09 1992-01-04 Aqueous solution for preparing the contrasting medium used in ultrasonic diagnosis and a method of its preparing
DK92901804T DK0566601T4 (en) 1991-01-09 1992-01-04 Echo contrast medium
JP50166892A JP3290655B2 (en) 1991-01-09 1992-01-04 Echo contrast agent
FI933137A FI119913B (en) 1991-01-09 1993-07-08 Echo Contrast Agent
US08347206 US5599523A (en) 1991-01-09 1994-11-22 Echo contrast agent

Publications (1)

Publication Number Publication Date
WO1992011873A1 true true WO1992011873A1 (en) 1992-07-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/000012 WO1992011873A1 (en) 1991-01-09 1992-01-04 Echo contrast agent

Country Status (11)

Country Link
US (1) US5599523A (en)
EP (2) EP0494615A1 (en)
JP (1) JP3290655B2 (en)
KR (1) KR100203221B1 (en)
CA (1) CA2098915C (en)
DE (1) DE4100470A1 (en)
DK (1) DK0566601T4 (en)
ES (1) ES2079176T5 (en)
FI (1) FI119913B (en)
RU (1) RU2091079C1 (en)
WO (1) WO1992011873A1 (en)

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WO1996026746A1 (en) * 1995-02-28 1996-09-06 Alliance Pharmaceutical Corp. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
US5558094A (en) * 1991-09-17 1996-09-24 Sonus Pharmaceuticals, Inc. Methods for using persistent gases as ultrasound contrast media
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